Elise Robinson and colleagues plan to develop and deploy the statistical methods needed to interpret genomic data from SPARK and other large autism spectrum disorder (ASD) datasets. They aim to identify causal variants, genes and pathways from ASD genome-wide association study (GWAS) results and characterize how they differ or converge with those that have been identified using exome sequencing data. Lastly, they plan to contrast the molecular basis of ASD with and without co-occurring intellectual disability.

A significant proportion of ASD risk genes encode proteins that function as chromatin modifiers. In the current project, Gaia Novarino plans to study conditional mouse models of two ASD risk genes in this class: ASH1L and KMT5B. She plans to study their roles during development and in adulthood, as well as assess whether any of the observed phenotypes are reversible. Such analyses are critical to developing novel therapeutic strategies for individuals with ASD associated with mutations in this class of genes.

Seizures are an extreme outcome of excitatory-inhibitory imbalance and are the most common neurological complication in autism spectrum disorder (ASD). Seizures are even more common in syndromic forms of ASD such as Angelman syndrome. In the current project, Ben Philpot’s laboratory aims to identify the circuitry and protein pathways underlying seizures in a mouse model of Angelman syndrome, with the goal of identifying disease-modifying targets to treat seizures. The mechanistic insights yielded by these studies may further guide therapeutically oriented investigations of excitatory-inhibitory imbalance across the broader spectrum of ASDs.

In the current project, Andreas Frick and Stefan Heinemann plan to investigate if big-conductance calcium- and voltage-activated potassium (BK_Ca) channel agonists could be a potential therapeutic treatment of atypical sensory experience in autism. These studies will be performed using a variety of in vitro and in vivo experimental systems, including human stem-cell derived neuronal models of autism and genetic mouse models of autism.

Genetics studies have identified many high-confidence risk genes for autism spectrum disorder (ASD). An important next step is to test the efficacy of different therapeutic approaches tailored to subtypes of ASD that are associated with mutations in specific risk genes. In the current project, Michael Boland and Wayne Frankel plan to assess the ability of three different genetic therapy strategies to correct multiple phenotypes in neurons derived from human induced pluripotent stem cells and mouse models of STXBP1 haploinsufficiency.

How neural information processing is affected in autism spectrum disorder (ASD) remains unclear. In the current project, Dan Feldman’s lab aims to identify how neural activity in the cerebral cortex differs across diverse genetic mouse models of ASD. Understanding these neural activity phenotypes will help identify the root cause of sensory and cognitive phenotypes in ASD.

Jingjing Li and Arnold Kriegstein aim to develop algorithms to identify mutations ablating gene regulation during brain development and to aggregate coding and noncoding variants for direct mapping onto clinical traits from personal genomes.

Neuronal activity triggers the expression of new genes that play a critical role in aspects of neural development and cognitive function. Building on evidence suggesting links between a class of ASD susceptibility loci (i.e., subunits of the BAF chromatin remodeling complex) and this form of gene regulation, Michael Greenberg and colleagues seek to determine whether disruption in neuronal activity-responsive chromatin remodeling underlies the effects of these ASD mutations.

Gloria Choi will use immunological and behavioral and systems neuroscience tools to gain a mechanistic understanding of how fever-associated immune activation could ameliorate behavioral phenotypes relevant to autism in a mouse model.

Arnold Kriegstein will apply single-cell RNA sequencing technologies to brain tissue samples from individuals with Dup15q syndrome, a genetically defined type of ASD, as well as to cerebral organoids derived from Dup15q-induced pluripotent stem cells. The goal of the project is to identify which cell types are affected by ASD during development and how this impacts mature brain circuits.